About

Timothy J. Lewis is a Professor in the Department of Mathematics at the University of California, Davis, where he has been a faculty member since 2004 and served as Vice-Chair from 2013 to 2017. He earned his Ph.D. in Mathematics from the University of Utah in 1998, with a dissertation focused on signal propagation in inhomogeneous excitable media under the supervision of Dr. James P. Keener. Prior to his doctoral studies, he completed an M.Sc. in Physiology at McGill University in 1991, where he researched cardiac conduction, and holds a B.Sc. in Physiology and Physics from McGill University as well. His postdoctoral work was conducted at New York University’s Center for Neural Science and Courant Institute of Mathematical Sciences from 1999 to 2004. Lewis's research interests lie at the intersection of applied mathematics and biology, with a particular focus on mathematical biology, neurobiology, cardiac electrophysiology, pharmacology, and excitable media. Throughout his career, he has contributed to the understanding of complex biological systems through mathematical modeling and analysis, emphasizing the dynamics of excitable media and their applications in physiology and medicine.

Research topics

• Medicine
• Internal medicine
• Neuroscience
• Biology
• Cell biology
• Endocrinology
• Biophysics
• Biochemistry
• Chemistry
• Cardiology
• Psychology

Selected publications

• Curvature-dependent onset of oscillations in excitable tissue

  Chaos An Interdisciplinary Journal of Nonlinear Science · 2025-06-01

  articleSenior author

  In cardiac tissue, the sinoatrial node (SAN) is responsible for initiating the periodic electrical pulses underlying heart beats. However, other heterogeneities (e.g., ischemic regions) can act as rogue pacemakers and produce oscillations in neighboring tissue that compete with the natural pacemaking of the SAN and cause potentially life-threatening arrhythmia. Thus, it is important to understand the physiological conditions that enable local regions of tissue to form pathological rhythms. It is well known that a small heterogeneity (a source) should not be able to easily activate a large area of excitable tissue (a sink). On a local level, this source-sink balance implies that positive curvature of a pacemaking region reduces the source-sink ratio and the ability to drive the neighboring tissue. However, while numerous studies provide evidence that supports the source-sink balance relationship, other studies have shown that for some depolarized heterogeneities, oscillations preferentially emerge from corners and other areas of high curvature. Here, we use an idealized two-domain reaction-diffusion system and a corresponding two-cell model to bridge the gap between these seemingly opposing viewpoints. In doing so, we identify the conditions for which curvature of a pacemaking region promotes or obstructs the production of oscillations in the neighboring tissue. Through our findings, we argue that the seemingly opposing views are, in fact, not contradictory, and the standard notion of source-sink balance is upheld, as long as we adapt a modified description of source and sink.

  PublisherDOI

• BPS2025 - A computational model of oxidative stress in a human ventricular myocyte

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• BPS2025 - A computational model of oxidative stress in a human ventricular myocyte

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• DO WIND FARM NOISE CONTROLS IN THE UK WORK?

  2024-12-06

  article1st authorCorresponding
  PublisherDOI

• Author Response: A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle

  2024-02-09

  peer-reviewOpen access

  Full text Figures and data Side by side Abstract eLife assessment eLife digest Introduction Results Discussion Materials and methods Data availability References Peer review Author response Article and author information Abstract The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in silico model, which we call the 'Hernandez–Hernandez model', of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of antihypertensive drugs. eLife assessment The study is of importance for the cardiac modeling field by developing a novel mathematical model with sex difference. The data are compelling, and the model is helpful for mechanistic understanding, and thus is also important for experimental physiology. The model is based on experimental data and validated against some experimental data. https://doi.org/10.7554/eLife.90604.3.sa0 About eLife assessments eLife digest High blood pressure is a major risk factor for heart disease, which is one of the leading causes of death worldwide. While drugs are available to control blood pressure, male and female patients can respond differently to treatment. However, the biological mechanisms behind this sex difference are not fully understood. Blood pressure is controlled by cells lining the artery walls called smooth muscle cells which alter the width of blood vessels. On the surface of smooth muscle cells are potassium and calcium channels which control the cell's electrical activity. When calcium ions enter the cell via calcium channels, this generates an electrical signal that causes the smooth muscle to contract and narrow the blood vessel. Potassium ions then flood out of the cell via potassium channels to dampen the rise in electrical activity, causing the muscle to relax and widen the artery. There are various sub-types of potassium and calcium channels in smooth muscle cells. Here, Hernandez-Hernandez et al. set out to find how these channels differ between male and female mice, and whether these sex differences could alter the response to blood pressure medication. The team developed a computational model of a smooth muscle cell, incorporating data from laboratory experiments measuring differences in cells isolated from the arteries of male and female mice. The model predicted that the sub-types of potassium and calcium channels in smooth muscle cells varied between males and females, and how the channels impacted electrical activity also differed. For instance, the potassium channel Kv2.1 was found to have a greater role in controlling electrical activity in female mice, and this sex difference impacted blood vessel contraction. The model also predicted that female mice were more sensitive than males to calcium channel blockers, a drug commonly prescribed to treat high blood pressure. The findings by Hernandez-Hernandez et al. provide new insights into the biological mechanisms underlying sex differences in response to blood pressure medication. They also demonstrate how computational models can be used to predict the effects of drugs on different individuals. In the future, these predictions may help researchers to identify better, more personalized treatments for blood pressure. Introduction Our primary objective was to develop and implement a novel computational model that comprehensively describes the essential mechanisms underlying electrical activity and Ca2+ dynamics in arterial myocytes. We aimed to uncover the key components necessary and sufficient to fully understand the behavior of arterial vascular smooth muscle myocytes and the cellular response to variations in pressure. The model represents the first-ever integration of sex-specific variations in voltage-gated KV2.1 and CaV1.2 channels, enabling the prediction of sex-specific disparities in membrane potential and the regulation of Ca2+ signaling in smooth muscle cells from systemic arteries. To further investigate sex-specific responses to antihypertensive medications, we extended our investigation to include a one-dimensional (1D) representation of tissue. This approach enabled us to simulate and forecast the effects of Ca2+ channel blockers within the controlled environment of an idealized mesenteric vessel. It is worth noting that this computational framework can be expanded to predict the consequences of antihypertensive drugs and other perturbations, transitioning seamlessly from single-cell to tissue-level simulations. Previous mathematical models (Jacobsen et al., 2007; Kapela et al., 2008; Yang et al., 2003; Parthimos et al., 1999) of vascular smooth muscle myocytes generated to describe the membrane potential and Ca2+ signaling in vascular smooth muscle cells have described the activation of G-protein-coupled receptors (GPCRs) by endogenous or pharmacological vasoactive agents activating inositol 1,4,5-trisphosphate (IP3) and ryanodine (RyR) receptors, resulting in the initiation of calcium waves. Earlier models have also provided insights into the contraction activation by agonists and the behavior of vasomotion. In a major step forward, the Karlin model (Karlin, 2015) incorporated new cell structure data and electrophysiology experimental data in a computational model that predicted the essential behavior of membrane potential and Ca2+ signaling arising from intracellular domains found in arterial myocytes. One notable limitation of earlier models is that they are based entirely on data from male animals. Furthermore, many data used to parameterize the Karlin model were obtained from smooth muscle from cerebral arteries. While cerebral arteries are important for brain blood flow, they do not control systemic blood pressure. Furthermore, they do not take into consideration the role of KV2.1 channels in the regulation of smooth muscle cell membrane potential. The function of the smooth muscle cells that wrap around small arteries is to regulate the diameter of these vessels. Arterial myocytes contract in response to increases in intravascular pressure (Bayliss, 1902). Based on work largely done using cerebral arterial smooth muscle, a model has been proposed in which this myogenic response is initiated when membrane stretch activates Na+-permeable canonical TRPC6 (Welsh et al., 2002; Spassova et al., 2006) and melastatin-type TRPM4 (Earley et al., 2004b; Earley et al., 2007). A recent study in smooth muscle from mesenteric arteries identified two additional TRP channels to the chain of events that link increases in intravascular pressure to arterial myocyte depolarization: TRPP1 (PKD1) and TRPP2 (PKD2) channels (Sharif-Naeini et al., 2009; Bulley et al., 2018). Together, these studies point to an elaborate multiprotein complex that plays a critical role in sensing pressure and initiating the myogenic response by inducing membrane depolarization and activating voltage-gated, dihydropyridine-sensitive L-type CaV1.2 Ca2+ channels (Moosmang et al., 2003; Knot and Nelson, 1998a). Ca2+ entry via a single or small cluster of CaV1.2 channels produces a local increase in intracellular free Ca2+ ([Ca2+]i) called a 'CaV1.2 sparklet' (Navedo and Santana, 2013; Navedo et al., 2005; Navedo et al., 2006; Amberg et al., 2007). Activation of multiple CaV1.2 sparklets produces a global increase in [Ca2+]i that activates myosin light chain kinase, which initiates actin-myosin cross-bridge cycling and thus contraction (Nelson et al., 1990). Negative feedback regulation of membrane depolarization and Ca2+ sparklet activation occurs through the activation of large-conductance, Ca2+-activated K+ (BKCa) channels as well as voltage-dependent KV2.1 and KV1.5/1.2 K+ channels (O'Dwyer et al., 2020; Amberg and Santana, 2006; Nelson et al., 1995; Plane et al., 2005). BKCa channels are organized into clusters along the sarcolemma of arterial myocytes (Sato et al., 2019) and are activated by Ca2+ sparks resulting from the simultaneous opening of ryanodine receptors type 2 (RyR2) located in a specialized junctional sarcoplasmic reticulum (SR) (Nelson et al., 1995; Ledoux et al., 2006; Brayden and Nelson, 1992; Jaggar et al., 1998a; Knot et al., 1998b). Because the input resistance of arterial myocytes is high (Pucovský and Bolton, 2006; Yuan et al., 1993) (about 2–10 GΩ), even relatively small currents (10–30 pA) produced by the activation of a small cluster (Nelson et al., 1995; Jaggar et al., 1998b; Wang et al., 2004) of 6–12 BKCa channels by a Ca2+ spark can transiently hyperpolarize the membrane potential of these cells by 10–30 mV. Accordingly, decreases in BKCa, KV1.2, KV1.5, and/or KV2.1 channels depolarize arterial myocytes, increasing CaV1.2 channel activity, [Ca2+]i, and contraction of arterial smooth muscle (Amberg and Santana, 2006; Zhong et al., 2010; Archer et al., 1998; Lu et al., 2002; Amberg et al., 2004). A recent study by O'Dwyer et al., 2020 suggested that KV2.1 channels have dual conducting and structural roles in mesenteric artery smooth muscle with opposing functional consequences. Conductive KV2.1 channels oppose vasoconstriction by inducing membrane hyperpolarization. Paradoxically, by promoting the structural clustering of the CaV1.2 channel, KV2.1 enhances Ca2+ influx and induces vasoconstriction. Interestingly, KV2.1 protein is expressed to a larger extent in female than in male arterial smooth muscle. This induced larger CaV1.2 clusters and activity in female than in male arterial myocytes. Here, we describe a new model, which we call the 'Hernandez–Hernandez model', of mesenteric smooth muscle myocytes that incorporates new electrophysiological and Ca2+ signaling data suggesting key sex-specific differences in male and female arterial myocytes. The model simulates membrane currents and their impact on membrane potential as well as local and global [Ca2+]i signaling in male and female myocytes. The Hernandez–Hernandez model predicts that KV2.1 channels play a critical, unexpectedly large role in the control of membrane potential in female myocytes compared to male myocytes. Importantly, our model predicts that clinically used antihypertensive CaV1.2 channel blockers cause larger reductions in CaV1.2 currents in female than in male arterial myocytes. Finally, we present a one-dimensional (1D) vessel representation of electrotonically coupled arterial myocytes connected in series. Predictions from the idealized vessel suggest that Ca2+ channel blockers are more potent in females, resulting in a more substantial [Ca2+]i reduction in female arterial smooth muscle compared to male. The Hernandez–Hernandez model demonstrates the importance of sex-specific differences in CaV1.2 and KV2.1 channels and suggests the fundamental electrophysiological and Ca2+-linked mechanisms of the myogenic tone. The model also points to testable hypotheses underlying differential sex-based pathogenesis of hypertension and distinct responses to antihypertensive agents. Results In this study, we developed a computational model of the electrical activity of an isolated vascular smooth muscle cell (Figure 1). A key goal was to optimize and validate the model with experimental data and then use the model to predict the effects of measured sex-dependent differences in the electrophysiology of smooth muscle myocytes. Figure 1 Download asset Open asset A schematic representation of the Hernandez–Hernandez model. The components of the model include major ion channel currents shown in purple including the voltage-gated L-type calcium current (ICa), nonselective cation current (INSC), voltage-gated potassium currents (IKv1.5 and IKv2.1), and the large-conductance Ca2+-sensitive potassium current (IBKCa). Currents from pumps and transporters are shown in red including the sodium/potassium pump current (INaK), sodium/calcium exchanger current (INCX), and plasma membrane ATPase current (IPMCA). Leak currents are indicated in green including the sodium leak current (INa,b), potassium leak current (IK,b), and calcium leak current (ICa,b). In addition, two currents in the sarcoplasmic reticulum are shown in orange: the sarcoplasmic reticulum Ca-ATPase current (ISERCA) and ryanodine receptor current (IRyR). Calcium compartments comprise three discrete regions including cytosol ([Ca]i), sarcoplasmic reticulum ([Ca]SR), and the junctional region ([Ca]Jun). Red stars (*) indicate measured sex-specific differences in ionic currents. In constructing the model, we first set out to measure the kinetics of the voltage-gated L-type CaV1.2 currents (ICa) in male and female myocytes using Ca2+ as the charge carrier as shown in Figure 2. These data provided information on the kinetics of Ca2+-dependent activation and inactivation of ICa. ICa is critical in determining cytosolic concentration [Ca2+]i in vascular mesenteric smooth muscle cells and is the predominant pathway for Ca2+ entry (Moosmang et al., 2003; Navedo and Santana, 2013; Navedo et al., 2005; Amberg et al., 2007; Knot et al., 1998b; Hill-Eubanks et al., 2011). Experiments using whole-cell patch-clamp were undertaken to measure the time constants of activation and deactivation (Figure 2A) and inactivation (Figure 2B) in male and female mesenteric artery smooth muscle cells shown as black and blue symbols, respectively. While the data from male (n = 10) and female (n = 12) myocytes showed comparable activation time constants, there was an observable trend of faster inactivation in the female cells in the lower voltage range, but the differences were not statistically significant. Steady-state activation and inactivation were also measured as shown in Figure 2C, with male data in black symbols and female as blue symbols. No observable differences in the gating characteristics of the male and female ICa were measured. Finally, the current–voltage relationship is shown from measurements in female (blue) and male (black) in Figure 2D. This analysis suggests that the amplitude of ICa was larger in female than in male myocytes over a wide range of membrane potentials. Figure 2 Download asset Open asset Experimentally measured and modeled L-type calcium currents (ICa) from male and female vascular smooth muscle (VSM) cells. Properties of ICa are derived from measurements in male and female VSM cells isolated from the mouse mesenteric arteries following voltage-clamp steps from –60 to 60 mV in 10 mV steps from a –80 mV holding potential. Experimental data is shown in black circles for male (n=10) and blue squares for female (n=12). Model fits to experimental data are shown with black solid lines for male and blue solid lines for female. (A) Male and female time constants of ICa activation. (B) Male and female time constants of ICa inactivation. (C) Male and female voltage-dependent steady-state activation and inactivation of ICa. (D) Current–voltage (I–V) relationship of ICa from male and female VSM myocytes. *p<0.05, **p<0.01, ***p<0.001. Error bars indicate mean ± SEM. We next used the experimental measurements to build and optimize a Hodgkin–Huxley model based on the data described above. The model includes voltage-dependent activation and inactivation gating variables, dL and dF, respectively. We modeled both gates following the approach by Kernik et al., 2019. It is important to note that smooth muscle cells operate within a voltage regime defined by the window current, which ranges between –45 mV and –20 mV. Under these conditions, [Ca2+]i remains below 1 μM. Therefore, we did not consider the Ca2+-dependent inactivation gating mode of the channel (Kapela et al., 2008; Fleischmann et al., 1994). The model of ICa is described by: (1) ICa=PCa∗dL∗dF∗zCa2F2VRT([Ca]iezcaFVRT−[Ca]outezcaFVRT−1) where PCa is the ion permeability, R is the gas constant, F is the Faraday's constant, and zCa is the valence of the Ca2+ ion. Parameters were optimized to male and female experimental data as shown for activation time constants (τactivation) and inactivation time constants (τinactivation) as solid lines in Figure 2A, B, respectively. Model optimization to male and female activation and inactivation curves are shown in Figure 2C. The model was also optimized to the ICa current–voltage (I–V) relationships shown as solid lines in Figure 2D. We next set out to determine sex differences in voltage-gated K+ currents (IK) in male and female mesenteric smooth muscle cells. IK is produced by the combined activation of KV and BKCa channels. Following the approach previously published by O'Dwyer et al., 2020, we quantified the contribution of KV (IKV) and BKCa (IBKCa) current to IK. K+ currents were recorded before and after the application of the channel blocker iberiotoxin (IBTX; 100 nm). Once identified the contribution IBKCa current, we isolated the voltage-gated potassium currents (IKV) whose contributors include the voltage-gated potassium channels KV1.5 and KV2.1. The presumed function of KV1.5 and KV2.1 channels on membrane potential is to produce delayed rectifier currents to counterbalance the effect of the inward currents (Nelson et al., 1990; O'Dwyer et al., 2020). Having isolated IKV, KV2.1 currents were identified using the application of the KV2.1 blocker ScTx1 (100 nM). As a result, the remaining ScTx1-insensitive component of the IKV current was attributed to KV1.5 channels. The results are shown in Figure 3. Experiments using whole-cell patch-clamp were undertaken to measure the steady-state activation G/Gmax of the KV2.1current (IKv2.1) as shown in Figure 3A in female (blue) and male (black) myocytes and no significant differences were observed. Measurements of time constants of activation (Figure 3B) of IKv2.1 in the voltage range of –30 to +40 mV in female (blue, n = 10) and male (black, n = 7) myocytes exhibited significant differences. Notably, activation time constants in male myocytes were smaller than those in female myocytes, corresponding to a faster activation rate in males. The current–voltage relationship of IKv2.1 is shown from measurements in female (blue, n = 20) and male (black, n = 10) myocytes in Figure 3C. Significant differences were observed in IKv2.1 at various voltages. In Figure 3C, data points without asterisks are not considered significant. Similarly, we measured the steady-state activation of the KV1.5 current (IKv1.5) as shown in Figure 3D where male and female experimental data in myocytes are shown with blue and black symbols. Properties of IKv1.5 steady-state activation G/Gmax show minimal sex-specific differences. The current–voltage relationship of IKv1.5 is shown from measurements in female (blue, n = 10) and male (black, n = 7) myocytes in Figure 3E. Finally, the current–voltage relationship of the contribution from IKv1.5 and IKv2.1 to the total voltage-gated current (IKVTOT) is shown in Figure 3F with male and female data shown with black and blue symbols, respectively. Data points in Figure 3D–F without asterisks are not significant. The table in Figure 3H summarizes the sex-dependent maximal conductance and the current response at specific voltages of –50, –40, –30, and –20 mV for both IKv1.5 and IKv2.1. Figure 3 Download asset Open asset Experimentally measured and modeled potassium currents (IKvTOT) from male and female vascular smooth muscle cells. The properties of IKv1.5 and IKv2.1 from experimental measurements in male and female vascular smooth muscle cells isolated from the mouse mesenteric arteries were recorded in response to voltage-clamp from –60 to 40 mV in 10 mV steps (holding potential –80 mV). Experimental data is shown as black circles for male and blue squares for female. Model fits to experimental data are shown with black solid lines for male and blue solid lines for female. (A) Male (n=7) and female (n=10) voltage-dependent steady-state activation of IKv2.1. (B) Male (n=7) and female (n=10) time constants of IKv2.1 activation. (C) Current–voltage (I–V) relationship of IKv2.1 from male (n=10) and female (n=20) myocytes. (D) Male (n=6) and female (n=10) voltage-dependent steady-state activation of IKv1.5. (E) Current–voltage (I–V) relationship of IKv1.5 from male (n=7) and female (n=10) myocytes. (F) Male (n=7) and female (n=10) total voltage-gated potassium current IKvTOT = IKv1.5 + IKv2.1. (G) Predicted male and female time constants of the IKv1.5 activation gate. (H) Table showing sex-specific differences in conductance and steady-state total potassium current–voltage dependence. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data points without asterisks are not significant. Error bars indicate mean ± SEM. To understand the contribution of each K+ current to the total voltage-gated current (IKVTOT) in mesenteric vascular smooth muscle cells, we built and optimized a Hodgkin–Huxley model to the data described above. First, we developed a model to describe the KV2.1 current. The optimized model to KV2.1 experimental data a voltage-dependent activation gating inactivation time is and is well by steady-state et al., we did not consider effects in our model. The model of IKv2.1 is described by where is the maximal conductance of KV2.1 channels and is the potential for Parameters were optimized to male and female experimental data as shown for activation curves in Figure Model optimization to male and female time constants of activation is shown as solid lines in Figure The model was also optimized to the IKv2.1 current–voltage (I–V) relationships shown as solid lines in Figure 3C. Similarly, we developed a model for The model was optimized to the KV1.5 experimental data and a voltage-dependent activation gating The model of IKv1.5 is described by where is the maximal conductance of KV1.5 channels and is the potential for Parameters were optimized to male and female experimental data as shown for activation curves in Figure The model was also optimized to the IKv1.5 current–voltage (I–V) relationships shown as solid lines in Figure 3E. we optimized the model to the time of KV currents. The model predicted that male and female myocytes have comparable time constants of activation in IKv1.5 as shown in Figure Finally, the optimized model of the total voltage-gated current (IKVTOT) is shown in Figure The total voltage-gated K+ current (IKvTOT) is the of and IKv2.1 described as Notably, the specific sex-specific differences observed in the total voltage-gated K+ current (IKvTOT) is to the sex-specific differences in the current produced by KV2.1 channels. We next the contribution of large-conductance potassium (BKCa) channels to vascular smooth muscle cell BKCa channels are activated by membrane depolarization or [Ca2+]i and are expressed in the membrane of vascular smooth muscle cells with and (Nelson et al., 1995; and 2005; et al., In smooth muscle cells, Ca2+ sparks are the physiological of BKCa channels. We on the by et al., that BKCa currents (IBKCa) are produced by two current one of and the other of and Experimental that BKCa channels with clusters in the plasma membrane in specialized junctional domains by the and the BKCa channels with with ryanodine receptors to in the junctional a Ca2+ [Ca2+]i from 10 to 100 BKCa channels et al., et al., Hill-Eubanks et al., Jaggar et al., et al., In our model, Ca2+ sparks are the physiological of BKCa channels. The mathematical of the BKCa with current was optimized to the experimental whole-cell electrophysiological data from and obtained at with a BKCa channel from and a from expressed in and 2005). Experimental data for steady-state activation and time constants of activation are shown in Figure and B, respectively. The activation gating on both voltage and junctional calcium The activation was from the model et al., 2011). The model of is described by where is the BKCa ion permeability, R is the gas constant, F is Faraday's constant, and is the of the potassium Model optimization to activation curves is shown with solid lines in Figure at three different 1 10 and 100 μM. The results from the steady-state activation measurements at 10 are also in with the experimental data in vascular myocytes in et al., which suggests that BKCa channels are to a mean junctional Ca2+ concentration of 10 μM. constants of activation were measured at = and our model was optimized and the shown in Figure as solid when the model was predicted = 10 as shown in Figure there was no effect of the in on the time The predicted current–voltage (I–V) relationships of are shown in Figure using three different 1 10 and 100 μM. We observed that the curves are similar at of 10 and 100 but when = 1 As the amplitude of the current shown in the curves in Figure is on the number of BKCa channels as and we set = 10 and simulated the curves using a BKCa cluster of and 10 channels. Figure Download asset Open asset Experimentally measured and modeled large-conductance Ca2+-activated K+ currents The model was optimized to data from and (A) activation of from experiments with three different 10 and 100 shown in green circles is the data from et al., (B) activation time constants with = and simulations = 10 μM. (C) at different of (D) with different cluster = and In vascular smooth muscle cells, the membrane potential over the physiological range of intravascular is than the potential of potassium = suggesting of inward currents by sodium conductance (Nelson et al., 1990; et al., et al., It has been that activating TRP channels nonselective currents that depolarize the membrane potential. We built a model for as and cation current to K+ and with = from model with a potential described by: where R is the gas constant, F is the Faraday's constant, is the and and are the intracellular sodium and potassium intracellular Similarly, and are the sodium and potassium The model of is described by where represents sodium current represents potassium current and and are the maximal of the sodium and potassium currents. In addition, we also models for leak currents of ion as where the

  PublisherDOI

• A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle

  eLife · 2024-02-09 · 1 citations

  articleOpen access

  The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in silico model, which we call the ‘Hernandez–Hernandez model’, of electrical and Ca 2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca 2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that K V 1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the K V 1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger K V 2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that K V 2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K + channels and L-type Ca 2+ channels are predicted to drive sex-specific differences in intracellular Ca 2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca 2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of antihypertensive drugs.

  PublisherDOI

• A multiscale predictive digital twin for neurocardiac modulation

  The Journal of Physiology · 2023 · 23 citations

  • Neuroscience
  • Cardiology
  • Medicine

  Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the β-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease.

  PublisherOA PDFDOI

• COMPARISON OF RECURSIVE BAYESIAN TRACKING ALGORITHMS FOR TRACKING SPERM WHALES

  2023-11-24

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Reviewer #1 (Public Review): A computational model predicts sex-specific responses to calcium channel blockers in mesenteric vascular smooth muscle

  2023-12-20

  peer-reviewOpen access

  The function of the smooth muscle cells lining the walls of systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in-silico model, which we call the "Hernandez-Hernandez model", of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of anti-hypertensive drugs.

  PublisherDOI

• A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-06-26 · 1 citations

  preprintOpen access

  Abstract The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in-silico model, which we call the “Hernandez-Hernandez model”, of electrical and Ca 2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca 2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that K V 1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the K V 1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger K V 2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that K V 2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K + channels and L-type Ca 2+ channels are predicted to drive sex-specific differences in intracellular Ca 2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca 2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of anti-hypertensive drugs.

  PublisherOA PDFDOI

Recent grants

• Dynamics in networks of cortical fast-spiking inhibitory interneurons

  NSF · $150k · 2005–2009

• Synchronous Activity in Networks of Electrically Coupled Cortical Interneurons

  NSF · $75k · 2009–2014

Frequent coauthors

• Colleen E. Clancy

  University of California, Davis

  39 shared

• Pei‐Chi Yang

  University of California, Davis

  31 shared

• Luis F. Santana

  University of California, Davis

  29 shared

• Samantha C. O’Dwyer

  University of California, Davis

  28 shared

• Collin Matsumoto

  University of California, Davis

  28 shared

• Mindy Tieu

  University of California, Davis

  28 shared

• Zhihui Fong

  University of California, Davis

  28 shared

• Gonzalo Hernandez-Hernandez

  University of California, Davis

  28 shared